Eltrombopag inhibits the proliferation of leukemia cells via reduction of intracellular iron and induction of differentiation

Abstract

Eltrombopag (EP) is a small-molecule, nonpeptide thrombopoietin receptor (TPO-R) agonist that has been approved recently for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenic purpura. Prior studies have shown that EP stimulates megakaryopoiesis in BM cells from patients with acute myeloid leukemia and myelodysplastic syndrome, and the results also suggested that it may inhibit leukemia cell growth. In the present study, we studied the effects of EP on leukemia cell proliferation and the mechanism of its antiproliferative effects. We found that EP leads to a decreased cell division rate, a block in G 1 phase of cell cycle, and increased differentiation in human and murine leukemia cells. Because EP is species specific in that it can only bind TPO-R in human and primate cells, these findings further suggested that the antileukemic effect is independent of TPO-R. We found that treatment with EP leads to a reduction in free intracellular iron in leukemic cells in a dose-dependent manner. Experimental increase of intracellular iron abrogated the antiproliferative and differentiation-inducing effects of EP, demonstrating that its antileukemic effects are mediated through modulation of intracellular iron content. Finally, determination of EP's antileukemic activity in vivo demonstrated its ability to prolong survival in 2 mouse models of leukemia. (Blood. 2012;120(2):386-394) IntroductionSurvival in acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) has remained poor despite recent efforts to treat patients with novel therapeutic regimens. [1][2][3][4] In addition, complications secondary to thrombocytopenia and bleeding occur frequently in AML and MDS, leading to significant morbidity and mortality. 5,6 Given that the median age of patients with AML is close to 70 years, novel antileukemia agents with limited BM toxicity are needed to improve outcomes.Eltrombopag (EP) is an oral, nonpeptide, small-molecule thrombopoietin receptor (TPO-R) agonist that has proven efficacy in treating chronic immune thrombocytopenic purpura (ITP) and hepatitis C-related thrombocytopenia. 7,8 Despite concerns that some leukemia blast cells express TPO-R, we and others have reported previously that EP does not stimulate leukemia or MDS cell growth, but may rather lead to a modest inhibition while continuing to stimulate normal megakaryopoiesis in BM samples of patients with AML or MDS. 9,10 One study using a close chemical derivative of EP found a toxic effect on myeloid leukemia cells, suggesting that the entire substance class, including EP itself, may possess antileukemic activity. 11 Studies using cell lines further suggested that the growth-inhibitory effect of EP is not related to expression levels of However, this hypothesis has not yet been formally tested, and the mechanism through which EP exerts its potential antileukemic effect is not known. The concentrations at which EP inhibits leukemia cell proliferation in vitro are clinically achievable with few side effects and hav...

Immune Thrombocytopenia - Current Diagnostics and Therapy: Recommendations of a Joint Working Group of DGHO, ÖGHO, SGH, GPOH, and DGTI

“…There are other publications that do not find a pro-leukemic effect [96]. In more recent MDS studies, TRAs had no effect on the rate of leukemic transformations [97].…”

Revealing eltrombopags promotion of human megakaryopoiesis through AKT/ERK-dependent pathway activation

“…48 On the other hand, recent studies concluded that eltrombopag allowed the formation of normal megakaryocytic colonies without the stimulation of malignant blasts from AML and MDS patients, and also had a strong anti-leukemic effect. 37,49 Interestingly, this effect was independent of c-Mpl, but was instead mediated through the modulation of intracellular iron content. 49 Finally, Kalota et al demonstrated that eltrombopag dramatically decreases ROS levels, leading to a disruption of AML intracellular metabolism and rapid cell death.…”

“…37,49 Interestingly, this effect was independent of c-Mpl, but was instead mediated through the modulation of intracellular iron content. 49 Finally, Kalota et al demonstrated that eltrombopag dramatically decreases ROS levels, leading to a disruption of AML intracellular metabolism and rapid cell death. 50 Thus, conflicting results were obtained concerning the potential leukemogenic effect of thrombopoietin mimetics, and further studies are required to clarify this important issue.…”

Induction of short-term remission with single agent eltrombopag in refractory nucleophosmin-1-mutated acute myeloid leukemia

“…3 However, in contrast to other thrombopoietin receptor (TPO-R, MPL) agonists, EPAG has also been shown in vitro to directly inhibit cell growth of leukemic cells while the underlying mechanisms are still under investigation. 5,6 There is still no formal proof of that observation in patients.…”